Genetic Deficiency and Biochemical Inhibition of ITK Affect Human Th17, Treg, and Innate Lymphoid Cells

Eken, Ahmet; Cansever, Murat; Somekh, Ido; Mizoguchi, Yoko; Zie̜tara, Natalia; Okuş, Fatma Zehra; Erdem, Serife; Canatan, Halit; Akyol, Şefika; Özcan, Alper; Karakükçü, Musa; Hollizeck, Sebastian; Rohlfs, Meino; Ünal, Ekrem; Klein, Christoph; Patıroğlu, Türkan

doi:10.1007/s10875-019-00632-5

Cited by 32 publications

(31 citation statements)

References 45 publications

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“…This is in concordance with other EBV-prone disorders [53]. Interestingly, in a study by Eken et al, reduced numbers of ILC2 and ILC3 together with Th17 cells were observed in an ITK-deficient patient [54].…”

Section: The Role Of Itk In Oncogenesissupporting

confidence: 76%

Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis

Lechner

Weigmann

2020

J Mol Med

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ITK (IL-2-inducible tyrosine kinase) belongs to the Tec family kinases and is mainly expressed in T cells. It is involved in TCR signalling events driving processes like T cell development as well as Th2, Th9 and Th17 responses thereby controlling the expression of pro-inflammatory cytokines. Studies have shown that ITK is involved in the pathogenesis of autoimmune diseases as well as in carcinogenesis. The loss of ITK or its activity either by mutation or by the use of inhibitors led to a beneficial outcome in experimental models of asthma, inflammatory bowel disease and multiple sclerosis among others. In humans, biallelic mutations in the ITK gene locus result in a monogenetic disorder leading to T cell dysfunction; in consequence, mainly EBV infections can lead to severe immune dysregulation evident by lymphoproliferation, lymphoma and hemophagocytic lymphohistiocytosis. Furthermore, patients who suffer from angioimmunoblastic T cell lymphoma have been found to express significantly more ITK. These findings put ITK in the strong focus as a target for drug development.

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Section: The Role Of Itk In Oncogenesissupporting

confidence: 76%

Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis

Lechner

Weigmann

2020

J Mol Med

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“…There are literature reports on more than 10 patients with ITK deficiency . All the patients developed recurrent EBV‐driven LPDs, including B‐cell lymphoma often of the Hodgkin type with (in many cases) lung involvement.…”

Section: Immunodeficiencies Causing Ebv‐driven B‐lymphoproliferative mentioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

113

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Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV -notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T-and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions. K E Y W O R D S B-cell lymphoproliferation, cell-cytotoxicity, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, primary immunodeficiency, T-cell proliferation | IMMUNE RE S P ON S E S TO EBV INFEC TI ONEpstein-Barr virus (EBV, also known as human herpesvirus 4) is a gamma herpes virus that only infects primates (primarily humans). 1,2 It is an encapsidated, double-stranded DNA virus with more than 100 genes. It is pandemic, since the great majority of human beings (>90%) have been infected by EBV. The main cell target is B lymphocytes that express CD21 -the membrane receptor for EBV entry through its 350 kDa major envelope glycoprotein. In immunocompetent adolescents and adults, EBV infection causes infectious mononucleosis (IM). Immunologically speaking, IM is characterized by a This article is part of a series of reviews covering Signaling and Signal Diversification in Immune

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“…In vivo, CD4 + T cells also preferentially differentiate into Tregs in ITK −/− mice [45]. Ibrutinib inhibits ITK, and was found to block ex vivo differentiation of healthy, naïve CD4 + T cells into Th17 [46]. FOXP3 + Tregs expand in response to low doses of ibrutinib, but are inhibited at higher doses [46].…”

Section: Th17 and Tregs Balancementioning

confidence: 99%

“…Ibrutinib inhibits ITK, and was found to block ex vivo differentiation of healthy, naïve CD4 + T cells into Th17 [46]. FOXP3 + Tregs expand in response to low doses of ibrutinib, but are inhibited at higher doses [46]. In patients receiving ibrutinib, a decrease of FOXP3 + Tregs was observed during the first two months of therapy [19,37].…”

Section: Th17 and Tregs Balancementioning

confidence: 99%

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Mhibik¹,

Wiestner²,

Sun³

2019

IJMS

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B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

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Genetic Deficiency and Biochemical Inhibition of ITK Affect Human Th17, Treg, and Innate Lymphoid Cells

Cited by 32 publications

References 45 publications

Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis

Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

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